Acquired immune responses are initiated by antigen presentation by antigen presenting cells (APC) and are regulated by T helper (TH) lymphocytes. TH1 cells are induced to develop by APC production of IL-12, produce IFNγ and IL-2 and are necessary for acquired cell-mediated responses. TH2 cells are thought to develop by APC production of IL-10 or PGE2, produce IL-4, IL-5, IL-6 and IL-10 and are necessary for acquired antibody immune responses. TNFα is produced by both TH1 and TH2 cells, although the largest source are macrophages, and appears to have an important role in delayed-type hypersensitivity (DTH) responses, an arm of cell-mediated immunity. Its production and effect in cell-mediated immunity is largely a function of the concomitant presence of IFNγ.
Antigen-specific immune responses in adults are thought to be almost entirely mediated by memory cells. Every arm of the adaptive immune system has associated memory cells: antibody-specific B lymphocytes, CTL and T helper lymphocytes that are essential to the development of antibody production and CTL activation. Memory cell-based responses are faster and larger than naïve responses (e.g., a strong response in five days compared with a weak response in ten days).
The effect of patient treatment on acquired immune responses are conveniently evaluated in an in vitro culture model of peripheral blood leukocytes (PBL). Treatment is given to a randomized population, blood is taken before and after treatment and antigen-specific immune responses measured in PBL cultured in the presence and absence of a memory antigen. The memory antigens chosen in the present invention were three live influenza viruses that the patient population would almost surely have encountered in the past two years. The inventors chose as indicators of immune response production of the cytokines IFNγ, IL-12, IL-10 and TNFα, plus production of the cytotoxic T lymphocyte (CTL) and natural killer (NK) cell granule product GrB, a cysteine protease that initiates apoptosis in killer cell targets. IFNγ, IL-2, IL-12 and GrB are measures of cell-mediated immune responses, while IL-10 is a measure of antibody-mediated immune responses. TNFα participates in cell-mediated immune responses but is more a measure of the innate defense (mostly macrophage) component of immune responses.
Many autoimmune diseases involve aberrant acquired cell-mediated immune responses to self antigens. Examples are Crohn's disease (a debilitating inflammatory bowel disease), the early stages of rheumatoid arthritis, Multiple Sclerosis and autoimmune diabetes (IDDM). In general, any treatment or condition that increases cell-mediated immune responses induces the flare of disease, while conditions suppressing cell-mediated immunity alleviate disease. For example, symptoms of rheumatoid arthritis are reduced by pregnancy, a condition that mutes cell-mediated immune responses. The symptoms flare again after delivery, when the immune system is thought to rebound toward its original balance of cell- and antibody-mediated immunity.